Age is the single most important risk factor for spontaneous neurodegenerative disease, including Parkinson's disease (PD). PD is characterized by a loss of functional nigrostriatal dopaminergic neurons. Age, in the absence of disease, is also associated with a decrease in functional neurons. Several aging factors have been implicated in the pathogenesis of dopaminergic neuronal loss including misfolding of the nerve terminal protein, alpha-synuclein. The long-term goal of our research program is to understanding how aging results in the accumulation of misfolded alpha-synuclein and loss of functional neurons and why the process is accelerated in those individuals that develop PD. In this project we aim to determine 1) if aging is associated with an accumulation of systemic neuronal alpha-synuclein 2) the factors that regulate alpha-synuclein synthesis and if aging affects these factors 3) and whether increasing clearance or decreasing synthesis of alpha-synuclein is of benefit in animals with spontaneous age-associated dopaminergic neurodegenerative disease. We will combine the unique resources of Oklahoma State University, Center for Veterinary Health Sciences and the University of Oklahoma Health Science Center to investigate the impact of age on synthesis and clearance of neuronal alpha-synuclein and its role in spontaneous neurodegenerative disease using two novel animal models;spontaneous dopaminergic neurodegeneration in aged baboons, and a highly prevalent dopaminergic neurodegenerative disease of aged equids. This project is designed to provide structured mentoring and training for the candidate, Dr. Dianne McFarlane, to acquire the skills needed to develop into a successful, independent researcher in comparative biomedical science. This project strives to identify the effect of aging on synthesis and clearance of the neuronal protein, alpha-synuclein, a protein whose aggregation is a central factor in the pathogenesis of PD. This project will test the efficacy of two novel treatments in reducing alpha-synuclein accumulation in animals with spontaneous dopaminergic neurodegenerative disease and will assess the ability of two unique peripheral markers to predict central neurodegeneration. Therefore, we expect the results of this project to improve available methods for diagnosis and treatment of Parkinson's disease.